Cited by 127Redox biology and oxidative stressGlutathione Transferases and PolymorphismsEnzyme Structure and Function

Crystal Structure of the Antioxidant Enzyme Glutathione Reductase Inactivated by Peroxynitrite

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Savvides, Savvas N., Scheiwein, Michael, Böhme, Catharina C., Arteel, Gavin E., Karplus, P. Andrew, Becker, Katja, Schirmer, R. Heiner·2002·Journal of Biological Chemistry

Abstract

As part of our studies on the nitric oxide-related pathology of cerebral malaria, we show that the antioxidative enzyme glutathione reductase (GR) is inactivated by peroxynitrite, with GR from the malarial parasite Plasmodium falciparum being more sensitive than human GR. The crystal structure of modified human GR at 1.9-A resolution provides the first picture of protein inactivation by peroxynitrite and reveals that this is due to the exclusive nitration of 2 Tyr residues (residues 106 and 114) at the glutathione disulfide-binding site. The selective nitration explains the impairment of binding the peptide substrate and thus the nearly 1000-fold decrease in catalytic efficiency (k(cat)/K(m)) of glutathione reductase observed at physiologic pH. By oxidizing the catalytic dithiol to a disulfide, peroxynitrite itself can act as a substrate of unmodified and bisnitrated P. falciparum glutathione reductase.

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Crossref · 10.1074/jbc.m108190200

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  • The function of GR can be oxidatively inactivated at a Cys residue in the active site.

    “Interestingly, the function of GR can be oxidatively inactivated at a Cys residue in the active site (372, 428).”

    From Redox regulation of mitochondrial function (2012) · cites this paper as [372]

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Authors
Savvides, S. N., Scheiwein, M., Böhme, C. C., Arteel, G. E., Karplus, P. A., Becker, K., & Schirmer, R. H.
Affiliations
  • Oregon State University (US)
  • Heidelberg University (DE)
  • Justus-Liebig-Universität Gießen (DE)
  • Heinrich Heine University Düsseldorf (DE)
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2002-01
Volume
277
Issue
4
Pages
2779-2784
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2068301733
Cited by
127
References
59
Citations by year
2026: 1 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 3 · 2018: 7 · 2017: 4 · 2016: 2 · 2015: 8 · 2014: 10 · 2013: 4 · 2012: 11
FWCI
2.21
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
Keywords
glutathione reductase, peroxynitrite, protein nitration, tyrosine nitration, Plasmodium falciparum, cerebral malaria, nitric oxide, enzyme inactivation, crystal structure, catalytic efficiency, antioxidant enzymes
MeSH terms
Animals, Antioxidants, Binding Sites, Catalysis, Disulfides, Dose-Response Relationship, Drug, Flavins, Glutathione Reductase, Humans, Hydrogen-Ion Concentration, Kinetics, Models, Molecular, Nitrogen, Peptides, Plasmodium falciparum, Protein Binding, Spectrophotometry, Toluene, Tyrosine, Signal Transduction, Crystallography, X-Ray, Peroxynitrous Acid

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